Insulin is a peptide secreted by the beta cells of the pancreas, and plays an important role in controlling the blood glucose level in the body. A metabolic disease, diabetes is associated with elevated blood glucose levels caused by an abnormality in the secretion or function of insulin. Type 1 diabetes is caused by elevated blood glucose levels due to failure in insulin production of the pancreas, and type 2 diabetes is caused by elevated blood glucose levels due to an abnormality in the secretion or function of insulin. Patients with type 2 diabetes are usually treated with oral hypoglycemic agents having a chemical substance as a main ingredient, and in some cases, given with insulin, whereas patients with type 1 diabetes require insulin treatment.
The most common insulin therapy involves insulin injections before and/or after meals. Currently, injectable insulin is available, and as a general rule, is given in a subcutaneous injection. The method of administration varies depending on its time course of action. Insulin injection shows a more rapid hypoglycemic effect than oral administration, and can be safely used when oral administration is not possible. Also, there is no dose limit for insulin use. However, long-term use of insulin three times a day can lead to disadvantages such as aversion to needles, difficulty in handling the injection device, hypoglycemia, and weight gain. Weight gain due to long-term use of insulin may increase the risk of cardiovascular disease and insulin resistance. Meanwhile, there are many efforts being made to maximize the efficacy by maintaining the long term, elevated levels of insulin peptide drugs after absorption by the body. For example, long-acting insulin formulations such as Lantus (Insulin glargine; Sanofi Aventis) and Levemir (Insulin detemir; Novo Nordisk) have been developed and are commercially available. Unlike insulin NPH (Neutral Protamine Hagedorn), these long-acting drugs reduce the risk of hypoglycemia during sleep, and Levemir in particular was associated with somewhat less weight gain. However, these drug formulations are also disadvantageous in that they must be given once or twice a day.
Meanwhile, one insulinotropic peptide, glucagon like peptide-1 (GLP-1), is an incretin hormone secreted by L-cells of the ileum and colon. Glucagon like peptide-1 functions to augment insulin release in a glucose-dependent manner so as to prevent hypoglycemic episodes. Owing to this property, it received attention as a potential treatment for type 2 diabetes. However, the primary obstacle to the use of GLP-1 as a therapeutic agent is its extremely short half-life of less than 2 minutes in plasma. Currently, exendin-4 is commercially available as a glucagon like peptide-1 receptor agonist, and it is a glucagon like peptide-1 analogue purified from the salivary gland of a gila monster. Exendin-4 has resistance to DPP IV (Dipeptidyl peptidase-4), and higher physiological activity than glucagon like peptide-1. As a result, it had an in-vivo half-life of 2 to 4 hours, which was longer than that of glucagon like peptide-1 (U.S. Pat. No. 5,424,286). However, with the method for increasing the resistance to DPP IV only, the physiological activity is not sufficiently sustained, and for example, in the case of commercially available exendin-4 (exenatide), it needs to be injected to a patient twice a day, and exenatide-treated patients still experience adverse events such as nausea and vomiting.
In order to solve the above problems, the present inventors suggested a long-acting peptide conjugate, which was prepared by linking a physiologically active polypeptide and an immunoglobulin Fc region via a non-peptidyl polymer as a linker by a covalent bond, thereby sustaining the activity and improving the stability of the protein drug at the same time (Korean Patent No. 10-0725315). In particular, they found that each of the long-acting insulin conjugate and the long-acting exendin-4 conjugate exerts remarkably increased in-vivo efficacy (Korean Patent Application Nos. 10-2008-0001479 and 10-2010-0054068).
However, there are still the problems of weight gain, or nausea and vomiting, when insulin or exendin-4 is injected in an amount which maintains a stable blood glucose level. Thus, there is an urgent need to develop a therapeutic method showing excellent therapeutic effects on diabetes with lower doses and less frequent use of the drug.